Remedy for dermatitis

ABSTRACT

A dermatitis-curing agent, characterized by comprising (A) a zinc compound and (B) at least one compound selected from the group consisting of multivalent unsaturated fatty acids and their esters as effective components is very effective for enteropathic acrodermatitis syndrome, and seborrheic dermatitis, psoriasis vulgaris, bullous dermatitis and puritus cutaneus, which show similar skin symptoms, or for symtoms due to zinc deficiency caused by injuries, burn injuries and frostbites.

TECHNICAL FIELD

The present invention relates to a dermatitis-curing agent.

BACKGROUND ART

Zinc (Zn) is a trace element contained in a high concentration next toiron throughout all the tissues and body fluids of human beings.

Physiological actions of zinc relate to, for example, growth, skeletongrowth, activation of metabolism of skin and its related organs,maintenance of reproductive functions, maintenance of gustatorysensation and olfactory sensation, effects on mental conditions andaction, improvement of immunological functions, etc.

Enteropathic acrodermatitis syndrome known as a recessive hereditarydisease, whose main symptom is a characteristic tetter, is obviously dueto zinc deficiency. Furthermore, it is reported that in the long-termintravenous zinc-deficient nutrition practice similar symptom toenteropathic acrodermatitis syndrome appears. Still furthermore, it isconfirmed and reported that even in skin diseases showing commonobservations to those of enteropathic acrodermatitis syndrome, such asseborrheic dermatitis, psoriasis vulgaris, bullous dermatitis, prurituscutaneus, etc. or even in case of injuries, burn injuries, frostbites, ablood zinc concentration is lowered, often resulting in zinc deficiency.

It is known, on the other hand, that when zinc is excessively taken in,there occur diarrhea, stomach erosion, decrease in plasma HDLcholesterol, etc. and in serious cases there occurs dehydration.

Fatty acids having 16 to 22 carbon atoms and at least two double bondssuch as linoleic acid, γ-linolenic acid, eicosapentaenoic acid (EPA),docosahexaenoic acid (DHA), arachidonic acid (Ara), dihomo-γ-linolenicacid (DGLA), etc. are called generally multivalent unsaturated fattyacids, and constitute cell membranes as major components and furthermoretake part in control of membrane fluidity, etc. Still furthermore, theyhave an antilipotropic action, an antiinflammatory action and anantithrombotic action. Still furthermore, they are important precursorsfor prostaglandins (PG) having functions to control an immunologicalsystem, a circulatory system, a hormone secretory system, etc.

There are many reports that linoleic acid has an action to retain waterin the skin and effects on prevention of adult diseases caused byexcessive intake of animal fat containing a large amount of saturatedfatty acids as one factor, such as an action to lower a bloodcholesterol concentration, an anti-cancer action, etc.

It is reported that γ-linolenic acid has a stronger action to lower ablood cholesterol concentration than linoleic acid, an anti-allergicaction, an effect on atopic dermatitis, control of fatty liver due toalcohol intake, relief of menstruation pain, etc.

It is reported that EPA has many physiological functions such as anantithrombotic action, an antilipotropic action, a hypotensive action,an antiinflammatory action, an anti-allergic action, etc.

It is reported that DHA has physiological actions on the cranial nervesystem such as an action to improve the visual acuity reduction, aneffect on improvement of memory and learning ability, an essentialcomponent of mother's milk for brain growth, etc.

It is reported that Ara has physiological actions such as an action asan essential fatty acid, an action to suppress skin psoriasis, an actionto protect the stomach wall, an action to lower a blood cholesterolconcentration, a liver-protecting action such as prevention of fattyliver, etc., an important substance for growth of fetal bodies orbrains, etc.

It is reported that DGLA has similar physiological actions to those ofγ-linolenic acid and further has an action as a PG1 group precursor andsuch physiological actions as an anti-thrombotic action, a hypotensiveaction, an anti-dyskinesia action, etc.

DISCLOSURE OF THE INVENTION

The present inventors have found that dermatitis caused by zincdeficiency can be improved at a much less zinc dose by administering acombination of a zinc compound with a multivalent unsaturated fatty acidor its esters, and have established the present invention.

An object of the present invention is to provide an effectivedermatitis-curing agent against enteropathic acrodermatitis syndrome,and skin diseases showing similar skin symptom such as seborrheicdermatitis, psoriasis vulgaris, bullous dermatitis and pruritus cutaneusor symptoms accompanied by zinc deficiency due to injuries, burninjuries and frostbites.

A dermatitis-curing agent according to the present invention ischaracterized by comprising (A) a zinc compound and (B) at least onecompound selected from the group consisting of multivalent unsaturatedfatty acids and their esters (which may be hereinafter referred to as"multivalent unsaturated fatty acids") as effective components.

Zinc compound for use in the present invention is organic acid salts orinorganic acid salts of zinc and specifically includes zinc sulfate,zinc gluconate, zinc chloride, zinc oxide, etc. Effective dose thereofis 1 to 50 mg, preferably 5 to 20 mg per day for a healthy adult as zinccontents.

Multivalent unsaturated fatty acid is fatty acids having 16 to 22 carbonatoms and at least two double bonds in the molecule, and preferably arelinoleic acid, γ-linolenic acid, EPA, DHA, Ara and DGLA, more preferablyEPA and DHA. Esters of multivalent unsaturated fatty acid include, forexample, triacylglycerides, ethyl esters, etc. Effective daily dose oflinoleic acid for a healthy adult is 100 mg to 35 g, preferably 300 mgto 20 g. Effective dose of γ-linolenic acid is 30 mg to 20 g, preferably50 mg to 10 g. Effective dose each of other multivalent unsaturatedfatty acids is 5 to 500 mg, preferably 20 to 250 mg.

In the present invention, mixing ratio by weight of zinc content tomultivalent unsaturated fatty acid is 1:20 to 1:1000, preferably 1:20 to1:200.

Zinc compound and multivalent unsaturated fatty acids as effectivecomponents of the present invention can be administered as they are, or,if desired, are mixed with other known additives, for example, asurfactant, a wetting agent, an antioxidant, a coloring agent, acorrigent, etc. and can be formulated into oral preparations such ascapsules, liquid preparations, etc. according to the conventionalmethod.

Surfactant includes, for example, glycerol, glycerol monostearate,monoglyceride, polyethylene hardened castor oil, polyoxyethylenehardened castor oil, sorbitan monostearate, sorbitan monopalmitate,sorbitan monolaurate, polyoxyethylene/polyoxypropylene block copolymer,polysolvates, methyl paraoxybenzoate, ethyl paraoxybenzoate, butylparaoxybenzoate, propyl paraoxybenzoate, sodium laurylsulfate,macrogols, sucrose fatty acid ester, lecithine, magnesium metasilicatealuminate, etc.

Wetting agent includes, for example, diisobutyl adipate, light liquidparaffin, D-sorbitol, propylene glycol, etc.

Antioxidant includes, for example, dibutylhydroxytoluene (BHT), propylgallate, butylhydroxyanisol (BHA), α-tocopherol, citric acid, etc.

Coloring agent includes, for example, tar colors, titanium oxide, etc.

Corrigent includes, for example, citric acid, adipic acid, ascorbicacid, menthol, purified sucrose, etc.

In case of liquid preparations, other physiologically active components,minerals, vitamins, amino acids, organ extracts, hormones, nutrients,perfumes, pH-adjusting agent, etc. can be added thereto to give anappropriate taste, if required.

Any additives as usually used in preparations can be supplemented, solong as they are pharmacologically acceptable.

Industrial Utility

The present dermatitis-curing agent is very effective for enteropathicacrodermatitis syndrome, and seborrheic dermatitis, psoriasis vulgaris,bullous dermatitis and pruritus cutaneus, which show similar skinsymptoms, or for symptoms due to zinc deficiency caused by injuries,burn injuries and frostbites.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a diagram showing correlations between inflamed area of skin(cm²) on the axis of ordinate and improvement ratios of skininflammation as determined for individual drugs on the axis of abscissa.

FIG. 2 is a diagram showing correlations between epidermal zincconcentration (ppm) on the axis of ordinate and increase ratio ofepidermal zinc concentration as determined for individual drugs on theaxis of abscissa.

FIG. 3 is a diagram showing correlations between TEWL [transepidemalwater loss (g/m² ·hr)] on the axis of ordinate and suppression ratio oftransepidermal water loss as determined for individual drugs on the axisof abscissa.

FIG. 4 is a diagram showing correlations between epidermal zincconcentration (ppm) on the axis of ordinate and increase ratio ofepidermal zinc concentration as determined for individual drugs on theaxis of abscissa.

FIG. 5 is a diagram showing correlations between linoleic acidconcentration (%) in ceramide on the axis of ordinate and increase ratioof linoleic acid concentration as determined for individual drugs on theaxis of abscissa.

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention will be described further in detail below,referring to Examples and Test Examples.

EXAMPLE 1

    ______________________________________                                        (Formulation)                                                                 ______________________________________                                        Zinc gluconate (trihydrate)                                                                          156.8  mg                                              Linoleic acid          15     g                                               γ-linolenic acid 5      g                                               ______________________________________                                    

The foregoing compounds were mixed with 10 to 20 g of monoglyceride,polyethylene hardened castor oil, sucrose fatty acid ester or lecithine,or their mixture, 5 ml of ethanol and such an amount of distilled wateras to make the total volume 100 ml in a mixer, and then the resultingmixture was emulsified in a homogenizer at 200 kg/cm³ to make 100 ml ofa liquid preparation.

EXAMPLE 2

    ______________________________________                                        (Formulation)                                                                 ______________________________________                                        Zinc sulfate (heptahydrate)                                                                          88.5   mg                                              Linoleic acid          15     g                                               ______________________________________                                    

The foregoing compounds were mixed with 5 to 15 g of monoglyceride,polyethylene hardened castor oil, sucrose fatty acid ester or lecithine,or their mixture, 3 ml of ethanol and such an amount of distilled wateras to make the total volume 100 ml in a mixer, and then the resultingmixture was emulsified in a homogenizer at 200 kg/cm³ to make 100 ml ofa liquid preparation.

EXAMPLE 3

    ______________________________________                                        (Formulation)                                                                 ______________________________________                                        Zinc gluconate (trihydrate)                                                                           156.8  mg                                             Bio-γ-linolenic acid oil (containing                                                            30     g                                              9.3 g of linoleic acid and 1.5 g of                                           γ-linolenic acid)                                                       ______________________________________                                    

The foregoing compounds were mixed with 10 to 30 g of monoglyceride,polyethylene hardened castor oil, sucrose fatty acid ester or lecithine,or their mixture, 5 ml of ethanol and such an amount of distilled wateras to make the total volume 100 ml in a mixer, and then the resultingmixture was emulsified in a homogenizer at 200 kg/cm³ to make 100 ml ofa liquid preparation.

EXAMPLE 4

    ______________________________________                                        (Formulation)                                                                 ______________________________________                                        Zinc sulfate (heptahydrate)                                                                          88.5   mg                                              Bio-γ-linolenic acid oil                                                                       20     g                                               ______________________________________                                    

The foregoing compounds were mixed with 5 to 20 g of monoglyceride,polyethylene hardened castor oil, sucrose fatty acid ester or lecithins,or their mixture, 5 ml of ethanol and such an amount of distilled waterto make the total volume 100 ml in a mixer, and then the resultingmixture was emulsified in a homogenizer at 200 kg/cm³ to make 100 ml ofa liquid preparation.

EXAMPLE 5

    ______________________________________                                        (Formulation)                                                                 ______________________________________                                        Zinc gluconate (trihydrate)                                                                           156.8  mg                                             Corn oil (containing 7.0 g of                                                                         20     g                                              linoleic acid)                                                                ______________________________________                                    

The foregoing compounds were mixed with 5 to 20 g of monoglyceride,polyethylene hardened caster oil, sucrose fatty acid ester or lecithine,or their mixture, 5 ml of ethanol and such an amount of distilled wateras to make the total volume 100 ml in a mixer, and then the resultingmixture was emulsified in a homogenizer at 200 kg/cm³ to make 100 ml ofa liquid preparation.

EXAMPLE 6

    ______________________________________                                        (Formulation)                                                                 ______________________________________                                        Zinc sulfate (heptahydrate)                                                                           88.5   mg                                             Pine nut oil (containing 5.7 g of                                                                     20     g                                              linoleic oil)                                                                 ______________________________________                                    

The foregoing compounds were mixed with 5 to 20 g of monoglyceride,polyethylene hardened castor oil, sucrose fatty acid ester or lecithine,or their mixture, 5 ml of ethanol and such an amount of distilled wateras to make the total volume 100 ml in a mixer, and then the resultingmixture was emulsified in a homogenizer at 200 kg/cm³ to make 100 ml ofa liquid preparation.

EXAMPLE 7

    ______________________________________                                        (Formulation)                                                                 ______________________________________                                        Zinc gluconate (trihydrate)                                                                            156.8  mg                                            Evening primrose (Oenothera tetraptera)                                       oil (containing 8.6 g of linoleic acid                                                                 20     g                                             and 2.1 g of γ-linolenic acid)                                          ______________________________________                                    

The foregoing compounds were mixed with 5 to 20 g of monoglyceride,polyethylene hardened castor oil, sucrose fatty acid ester or lecithine,or their mixture, 5 ml of ethanol and such an amount of distilled wateras to make the total volume 100 ml in a mixer, and then the resultingmixture was emulsified in a homogenizer at 200 kg/cm³ to make 100 ml ofa liquid preparation.

EXAMPLE 8

    ______________________________________                                        (Formulation)                                                                 ______________________________________                                        Zinc sulfate (heptahydrate)                                                                           88.5   mg                                             Perilla (Perilla ocimoides) oil                                                                       20     g                                              (containing 5.7 g of linoleic acid)                                           ______________________________________                                    

The foregoing compounds were mixed with 5 to 20 g of monoglyceride,polyethylene hardened castor oil, sucrose fatty acid ester or lecithine,or their mixture, 5 ml of ethanol and such an amount of distilled wateras to make the total volume 100 ml in a mixer, and then the resultingmixture was emulsified in a homogenizer at 200 kg/cm³ to make 100 ml ofa liquid preparation.

EXAMPLE 9

    ______________________________________                                        (Formulation)                                                                 ______________________________________                                        In 7 capsules,                                                                Zinc oxide              25 mg                                                 γ-Linolenic acid  5000 mg                                               Magnesium metasilicate aluminate                                                                      327 mg                                                Polysolvate 60          227 mg                                                Propylene glycol        26 mg                                                 ______________________________________                                    

The foregoing compounds were weighed out and uniformly mixed. Then, 560mg each of the resulting mixture was filled into soft elastic capsulesor soft capsules to obtain 7 capsules.

EXAMPLE 10

    ______________________________________                                        (Formulation)                                                                 ______________________________________                                        In ten capsules,                                                              Zinc oxide              18.8 mg                                               Linoleic acid           5000 mg                                               γ-Linolenic acid  1500 mg                                               Magnesium metasilicate aluminate                                                                      427 mg                                                Polysolvate 60          300 mg                                                Propylene glycol        38 mg                                                 ______________________________________                                    

The foregoing compounds were weighed out and uniformly mixed. Then, 560mg each of the resulting mixture was filled into soft elastic capsulesor soft capsules to obtain 10 capsules.

EXAMPLE 11

    ______________________________________                                        (Formulation)                                                                 ______________________________________                                        In 14 capsules,                                                               Zinc oxide              6.3 mg                                                Linoleic acid           5000 mg                                               γ-Linolenic acid  1500 mg                                               Vitamin B.sub.2         24 mg                                                 Vitamin B.sub.6         100 mg                                                Nicotinic acid amide    60 mg                                                 Vitamin C               180 mg                                                Magnesium metasilicate aluminate                                                                      470 mg                                                Polysolvate 60          330 mg                                                Propylene glycol        42 mg                                                 Wheat germ oil          127.5 mg                                              ______________________________________                                    

The foregoing compounds were weighed out and uniformly mixed. Then, 560mg each of the resulting mixture was filled into soft elastic capsulesor soft capsules to obtain 14 capsules.

EXAMPLE 12

    ______________________________________                                        (Formulation)                                                                 ______________________________________                                        In 11 capsules,                                                               Zinc oxide              6.3 mg                                                Linoleic acid           5000 mg                                               Vitamin B.sub.2         24 mg                                                 Vitamin B.sub.6         100 mg                                                Nicotinic acid amide    60 mg                                                 Vitamin C               180 mg                                                Magnesium metasilicate aluminate                                                                      370 mg                                                Polysolvate 60          260 mg                                                Propylene glycol        33 mg                                                 Wheat germ oil          128 mg                                                ______________________________________                                    

The foregoing compounds were weighed out and uniformly mixed. Then, 560mg each of the resulting mixture was filled into soft elastic capsulesor soft capsules to obtain 11 capsules.

EXAMPLE 13

    ______________________________________                                        (Formulation)                                                                 ______________________________________                                        In 4 capsules,                                                                Zinc oxide              6.3 mg                                                γ-Linolenic acid  1500 mg                                               Vitamin B.sub.2         24 mg                                                 Vitamin B.sub.6         100 mg                                                Nicotinic acid amide    60 mg                                                 Vitamin C calcium       180 mg                                                Magnesium metasilicate aluminate                                                                      135 mg                                                Polysolvate 60          95 mg                                                 Propylene glycol        12 mg                                                 Wheat germ oil          129 mg                                                ______________________________________                                    

The foregoing compounds were weighed out and uniformly mixed. Then, 560mg each of the resulting mixture was filled into soft elastic capsulesor soft capsules to obtain 4 capsules.

EXAMPLE 14

    ______________________________________                                        (Formulation)                                                                 ______________________________________                                        In 20 capsules,                                                               Zinc oxide              6.3 mg                                                Linoleic acid           5000 mg                                               γ-Linolenic acid  1500 mg                                               Vitamin B.sub.2         24 mg                                                 Vitamin B.sub.6         100 mg                                                Biotin                  0.5 mg                                                Pantothenic acid        30 mg                                                 Coix extract            3000 mg                                               Nicotinic acid amide    60 mg                                                 Vitamin C               180 mg                                                Magnesium metasilicate aluminate                                                                      135 mg                                                Polysolvate 60          95 mg                                                 Propylene glycol        12 mg                                                 Wheat germ oil          129 mg                                                ______________________________________                                    

The foregoing compounds were weighed out and uniformly mixed. Then, 560mg each of the resulting mixture was filled into soft elastic capsulesor soft capsules to obtain 20 capsules.

EXAMPLE 15

    ______________________________________                                        (Formulation)                                                                 ______________________________________                                        In 19 capsules,                                                               Zinc oxide              6.3 mg                                                Linoleic acid           5000 mg                                               γ-Linolenic acid  1500 mg                                               Ferrous fumarate        15.2 mg                                               Magnesium carbonate     200 mg                                                Coix extract            2000 mg                                               Taurine                 500 mg                                                Royal jelly             100 mg                                                Vitamin B.sub.2         2.5 mg                                                Vitamin B.sub.6         5 mg                                                  Anhydrous caffeine      50 mg                                                 Magnesium metasilicate aluminate                                                                      670 mg                                                Polysolvate 60          470 mg                                                Propylene glycol        60 mg                                                 Wheat germ oil          127.5 mg                                              ______________________________________                                    

The foregoing compounds were weighed out and uniformly mixed. Then, 560mg each of the resulting mixture was filled into soft elastic capsulesor soft capsules to obtain 19 capsules.

EXAMPLE 16

    ______________________________________                                        (Formulation)                                                                 ______________________________________                                        Zinc gluconate (trihydrate)                                                                          1.57   g                                               Oil component *        60.0   g                                               Sucrose fatty acid ester                                                                             4.8    g                                               Glycerol monostearate  7.2    g                                               Glycerol               18.0   g                                               Ethanol                20.0   g                                               Purified sucrose       100.0  g                                               Butyl paraoxybenzoate  0.1    g                                               Purified water to make the                                                                           1000   ml                                              total volume                                                                  ______________________________________                                         * Neutral lipid containing 5 g of DHA, 5 g of EPA, 5 g of DGLA and 5 g of     Ara.                                                                     

0.1 g of butyl paraoxybenzoate was added to 500 ml of purified water anddissolved therein with heating. Then, 100 g of purified sucrose wasadded thereto with stirring to obtain a homogenous mixture. Aftercooling, 1.45 g of zinc gluconate was added, followed by adjusting pH to4.7 with a pH-adjusting agent to obtain a first mixture. Furthermore,4.8 g of sucrose fatty acid ester, 7.2 g of glycerol monostearate, 18.0g of glycerol, 20.0 g of ethanol and 60.0 g of oil component were mixedtogether with heating and uniform stirring, and after cooling, 100 ml ofpurified water was added thereto, and the mixture was homogeneouslystirred in a pressure homogenizer to obtain an emulsion composition. Theemulsion composition was mixed with the first mixture and homogenized inthe pressure homogenizer, followed by addition of purified water toobtain 1000 ml of a liquid preparation.

EXAMPLE 17

    ______________________________________                                        (Formulation)                                                                 ______________________________________                                        Zinc sulfate (heptahydrate)                                                                            88.5 mg                                              DHA                      500 mg                                               Magnesium metasilicate aluminate                                                                       65 mg                                                Polysolvate 60           45 mg                                                Propylene glycol         5 mg                                                 ______________________________________                                    

The foregoing compounds were weighed out and uniformly mixed. Then, theresulting mixture was evenly filled into soft elastic capsules or softcapsules, each of 400 mg to obtain 2 capsules.

EXAMPLE 18

    ______________________________________                                        (Formulation)                                                                 ______________________________________                                        Zinc gluconate (trihydrate)                                                                           156.8 mg                                              Ara                     500 mg                                                Magnesium metasilicate aluminate                                                                      65 mg                                                 Polysolvate 60          45 mg                                                 Propylene glycol        5 mg                                                  ______________________________________                                    

The foregoing compounds were weighed out and uniformly mixed. Then, theresulting mixture was evenly filled into soft elastic capsules or softcapsules, each of 400 mg to obtain 2 capsules.

EXAMPLE 19

    ______________________________________                                        (Formulation)                                                                 ______________________________________                                        Zinc gluconate (trihydrate)                                                                           156.8 mg                                              DGLA                    500 mg                                                Magnesium metasilicate aluminate                                                                      65 mg                                                 Polysolvate 60          45 mg                                                 Propylene glycol        5 mg                                                  ______________________________________                                    

The foregoing compounds were weighed out and uniformly mixed. Then, theresulting mixture was evenly filled into soft elastic capsules or softcapsules, each of 400 mg to obtain 2 capsules.

EXAMPLE 20

    ______________________________________                                        (Formulation)                                                                 ______________________________________                                        Zinc sulfate (heptahydrate)                                                                            22.1 mg                                              DHA                      400 mg                                               EPA                      400 mg                                               Magnesium metasilicate aluminate                                                                       65 mg                                                Polysolvate 60           45 mg                                                Propylene glycol         5 mg                                                 ______________________________________                                    

The foregoing compounds were weighed out and uniformly mixed. Then, theresulting mixture was evenly filled into soft elastic capsules or softcapsules, each of 350 mg to obtain 3 capsules.

EXAMPLE 21

    ______________________________________                                        (Formulation)                                                                 ______________________________________                                        Zinc sulfate (heptahydrate)                                                                            22.1 mg                                              Ara                      400 mg                                               DGLA                     400 mg                                               Magnesium metasilicate aluminate                                                                       65 mg                                                Polysolvate 60           45 mg                                                Propylene glycol         5 mg                                                 ______________________________________                                    

The foregoing compounds were weighed out and uniformly mixed. Then, theresulting mixture was evenly filled into soft elastic capsules or softcapsules, each of 350 mg to obtain 3 capsules.

EXAMPLE 22

    ______________________________________                                        (Formulation)                                                                 ______________________________________                                        Zinc gluconate (trihydrate)                                                                            39.2 mg                                              DHA                      250 mg                                               EPA                      250 mg                                               Ara                      250 mg                                               DGLA                     250 mg                                               Vitamin B.sub.2          24 mg                                                Vitamin B.sub.6          100 mg                                               Nicotinic acid amide     60 mg                                                Vitamin C                180 mg                                               Magnesium metasilicate aluminate                                                                       130 mg                                               Polysolvate 60           90 mg                                                Propylene glycol         10 mg                                                ______________________________________                                    

The foregoing compounds were weighed out and uniformly mixed. Then, theresulting mixture was evenly filled into soft elastic capsules or softcapsules, each of 350 mg to obtain 5 capsules.

EXAMPLE 23

    ______________________________________                                        (Formulation)                                                                 ______________________________________                                        Zinc sulfate (heptahydrate)                                                                            22.1 mg                                              DHA                      250 mg                                               EPA                      250 mg                                               Vitamin B.sub.2          24 mg                                                Vitamin B.sub.6          100 mg                                               Nicotinic acid amide     60 mg                                                Vitamin C calcium        180 mg                                               Magnesium metasilicate aluminate                                                                       98 mg                                                Polysolvate 60           68 mg                                                Propylene glycol         8 mg                                                 ______________________________________                                    

The foregoing compounds were weighed out and uniformly mixed. Then, theresulting mixture was evenly filled into soft elastic capsules or softcapsules, each of 350 mg to obtain 3 capsules.

EXAMPLE 24

    ______________________________________                                        (Formulation)                                                                 ______________________________________                                        Zinc gluconate (trihydrate)                                                                            39.2 mg                                              Ara                      250 mg                                               DGLA                     250 mg                                               Vitamin B.sub.2          24 mg                                                Vitamin B.sub.6          100 mg                                               Nicotinic acid amide     60 mg                                                Vitamin C calcium        180 mg                                               Magnesium metasilicate aluminate                                                                       98 mg                                                Polysolvate 60           68 mg                                                Propylene glycol         8 mg                                                 ______________________________________                                    

The foregoing compounds were weighed out and uniformly mixed. Then, theresulting mixture was evenly filled into soft elastic capsules or softcapsules, each of 400 mg to obtain 3 capsules.

EXAMPLE 25

    ______________________________________                                        (Formulation)                                                                 ______________________________________                                        Zinc sulfate (heptahydrate)                                                                        0.44     g                                               Oil component *      30.0     g                                               Vitamin B.sub.2      0.24     g                                               Vitamin B.sub.6      1.0      g                                               Biotin               5.0      mg                                              Panthotenic acid     0.30     g                                               Coix extract         20.0     g                                               Nicotinic acid amide 0.6      g                                               Vitamin C            1.8      g                                               Sucrose fatty acid ester                                                                           2.4      g                                               Glycerol monostearate                                                                              3.6      g                                               Glycerol             9.0      g                                               Ethanol              10.0     g                                               Purified sucrose     100.0    g                                               Butyl paraoxybenzoate                                                                              0.1      g                                               pH-adjusting agent   appropriate amount                                       Perfume              trace                                                    Purified water to make the                                                                         1000     ml.                                             total volume                                                                  ______________________________________                                         * Neutral lipid containing 5 g of DHA and 5 g of EPA.                    

0.1 g of butyl paraoxybenzoate was added to 500 ml of purified water anddissolved therein with heating, and 100 g of purified sucrose was addedthereto with stirring to obtain a homogenous mixture. After cooling,0.44 g of zinc sulfate was added, followed by adjusting pH to 4.7 with apH-adjusting agent to obtain a first mixture. Furthermore, 2.4 g ofsucrose fatty acid ester, 3.6 g of glycerol monostearate, 9.0 g ofglycerol, 10.0 g of ethanol and 30.0 g of oil component were mixed withheating and uniform stirring, and after cooling, 100 ml of purifiedwater was added thereto and the mixture was homogeneously stirred in apressure homogenizer to obtain an emulsion composition. The emulsioncomposition was mixed with the first mixture and homogenized in thepressure homogenizer, followed by addition of purified water to obtain1000 ml of a liquid preparation.

EXAMPLE 26

    ______________________________________                                        (Formulation)                                                                 ______________________________________                                        Zinc gluconate (trihydrate)                                                                        0.39     g                                               Oil component *      30.0     g                                               Iron ammonium citrate                                                                              0.3      g                                               Magnesium aspartate  5.95     g                                               Coix extract         20.0     g                                               Taurine              5.0      g                                               Royal jelly          1.0      g                                               Vitamin B.sub.2      25.0     mg                                              Vitamin B.sub.6      50.0     mg                                              Anhydrous caffeine   0.5      g                                               Sucrose fatty acid ester                                                                           2.4      g                                               Glycerol monostearate                                                                              3.6      g                                               Glycerol             9.0      g                                               Ethanol              10.0     g                                               Purified sucrose     100.0    g                                               Butyl paraoxybenzoate                                                                              0.1      g                                               pH-adjusting agent   appropriate amount                                       Perfume              trace                                                    Purified water to make                                                                             1000     ml                                              the total volume                                                              ______________________________________                                         * Neutral lipid containing 5 g of DGLA and 5 g of Ara.                   

0.1 g of butyl paraoxybenzoate was added to 500 ml of purified water anddissolved therein with heating, and 100 g of purified sucrose was addedthereto with stirring to obtain a homogeneous mixture. After cooling,0.39 g of zinc gluconate was added thereto, followed by adjusting pH to4.7 with a pH-adjusting agent to obtain a first mixture. Furthermore,2.4 g of sucrose fatty acid ester, 3.6 g of glycerol monostearate, 9.0 gof glycerol, 10.0 g of ethanol and 30.0 g of oil component were mixedwith heating and uniform stirring, and after cooling, 100 ml of purifiedwater was added thereto and the mixture was homogeneously stirred in apressure homogenizer to obtain an emulsion composition. The emulsioncomposition was mixed with the first mixture and homogenized in thepressure homogenizer, followed by addition of purified water to obtain1000 ml of a liquid preparation.

EXAMPLE 27

    ______________________________________                                        (Formulation)                                                                 ______________________________________                                        Zinc oxide               6.3 mg                                               DHA                      500 mg                                               Magnesium metasilicate aluminate                                                                       65 mg                                                Polysolvate 60           45 mg                                                Propylene glycol         5 mg                                                 ______________________________________                                    

The foregoing compounds were weighed out and uniformed mixed. Then, theresulting mixture was evenly filled into soft elastic capsules or softcapsules, each of 400 mg to obtain 2 capsules.

TEST EXAMPLE 1

(Test materials)

1 4 week-old, male hairless rats were divided into 5 groups and fed withtest feed having a zinc concentration of 3.5 ppm for 4 weeks.

Then, the rats were further bred with test feed containing 10% ofevening primrose oil, perilla oil, Bio γ-linolenic acid oil, pine nutoil or corn oil and having a zinc concentration of 4.5 ppm for 4 weeksto observe skin states.

Control 1 were rats bred with test feed having a zinc concentration of3.5 ppm for 4 weeks and further bred with test feed containing palm oilwithout linoleic acid, γ-linolenic acid and their esters as effectivecomponents and having a zinc concentration of 4.5 ppm for 8 weeks toobserve skin states.

2 Control 2 were rats bred at a zinc concentration of 20 ppm without oilfeeding for 4 weeks to observe skin states.

(Test procedure)

1 Observation of skin state:

After test breeding, a film was put over the back of rat to trace theinflamed parts, and then weight of inflamed parts was measured tocalculate the inflamed area.

2 Quantitative determination of essential fatty acids:

1.5 ml of an ice-cooled aqueous 2M KCl/0.1M EDTA solution was added to0.5 ml of plasma, and further 5 ml of methanol and 2.5 ml of chloroformwere added thereto, followed by mixing with a Boltic mixer for 2minutes. Then, the resulting mixture was centrifuged at 3000 rpm for 10minutes to separate it into two layers. The lower chloroform layer waswashed with 2M KCl and then with water and centrifuged. Then, thechloroform layer was concentrated to dryness at 35° C. in a nitrogen gasstream, and after immediate addition of 20 μl of chloroform (containing0.01 BHT), preserved at -20° C.

Analysis was carried out by gas chromatography with a column (megaporecolumn DB-23 made by J & W).

3 Quantative determination of skin zinc concentration:

About 20 mg of epidermis was exactly weighed out into a desalted Tefloncrucible and subjected to an acid decomposition under pressure in 1 mlof concentrated nitric acid at 100° C. for 4 hours to obtain testsamples. Quantitative determination of the metal was carried out by aflame method using an atomic absorption spectrometry (model Hitachi8100).

(Results)

Test results are shown in Tables 1 and 2, and FIGS. 1 and 2.

                                      TABLE 1                                     __________________________________________________________________________                Evening  Bio γ-                                                     Perilla                                                                           primrose                                                                           Pine                                                                              linolenic                                                                          Corn                                                                             Control                                          Fatty acid                                                                            oil oil  nut oil                                                                           acid oil                                                                           oil                                                                              1   Control 2                                    __________________________________________________________________________    Linoleic acid                                                                         28.4                                                                              43.06                                                                              28.44                                                                             30.92                                                                              35.10                                                                            --  --                                           (18:2 ω6)                                                               γ-Linolenic acid                                                                --  10.42                                                                              --  5.09 -- --  --                                           (18:3 ω6)                                                               γ-Linolenic acid                                                                 19.70                                                                             7.68                                                                              7.68                                                                              7.68 9.60                                                                             --  --                                           (18:3 ω3)                                                               Inflamed area                                                                         18.2                                                                              17.9 2.6 2.1  0.9                                                                              15.0                                                                              0.9                                          Zn concentration                                                                      3.5 ppm for 4 weeks (former half period)                                                               20 ppm                                       as fed  4.5 ppm for 4 weeks (latter half period)                                                               (for 8 weeks)                                __________________________________________________________________________

                  TABLE 2                                                         ______________________________________                                        Fatty acid    Epidermal zinc concentration (ppm)                              ______________________________________                                        Perilla oil   56.8 ± 11.4                                                  Evening primrose oil                                                                        60.6 ± 1.3                                                   Pine nut oil  72.3 ± 6.3                                                   Bio γ-linolenic acid oil                                                              89.7 ± 13.9                                                  Corn oil      98.5 ± 11.4                                                  Control 1     59.3 ± 2.1                                                   Control 2     91.3 ± 10.2                                                  ______________________________________                                         Controls 1 and 2 are the same as in Table 1.                             

Rats suffering from skin diseases caused by breeding with zinc-deficientfeed (Zn: 3.5 ppm) for 4 weeks were bred with low-zinc feeds (Zn: 4.5ppm) containing one of 5 kinds of oils having different fatty acidcompositions. As a result, Bio γ-linolenic acid oil containing 26.5 to52.8% of linoleic acid and 5.0 to 7.6% of γ-linolenic acid could improvethe skin inflammation, as compared with control 1 (low-zinc feedcontaining palm oil).

Pine nut oil and corn oil containing no γ-linolenic acid, but containing26.5 to 52.8% of linoleic acid could also improve the skin inflammation,as compared with control 1. Corn oil showed an improvement equivalent tothat of control 2 (bred with 20 ppm Zn).

Evening primrose oil containing 26.7 to 52.8% of linoleic acid and over8% of γ-linolenic acid showed no improvement of skin inflammation, ascompared with control 1. Perilla oil containing linoleic acid within therange and a large amount of α-linolenic acid showed no improvement ofskin inflammation, as compared with control 1.

In the quantitative determination of epidermal zinc concentration, oil,showing a smaller inflamed area and thus a tendency of improvement had atendency of higher epidermal zinc concentration.

TEST EXAMPLE 2

(Test materials)

1 4-week old, male hairless rats were divided into two groups, and onegroup was bred with test feed having a zinc concentration of 3.5 ppm andcontaining DHA (2.72 mg/100 mg feed) for 4 weeks, while other group wasbred with test feed containing EPA (2.56 mg/100 mg feed) for 4 weeks, toobserve skin state.

2 Control 1 was bred with test feed having a zinc concentration of 3.5ppm and containing 10% of corn oil (without EPA and DHA) for 4 weeks toobserve skin state.

3 Control 2 was bred with test feed having a zinc concentration of 20ppm and 10% of corn oil (without EPA and DHA) for 4 weeks to observeskin state.

(Test procedure)

1 Transepidermal water loss (TEWL):

Transepidermal water loss was measured by an impedance meter modelSKICON-200 (made by IBS Co.). Degree of improvement of rough, dry skinwas judged from results of TEWL and visual observation of deteriorationdegree of skin state (for those with recognized inflamed sites).

2 Quantitative determination of epidermal zinc concentration:

About 20 mg of epidermis was exactly weighed out into a desalted Tefloncrucible and subjected to an acid decomposition under pressure in 1 mlof concentrated nitric acid at 100° C. for 4 hours to obtain testsamples. Quantative determination of the metal was carried out by aflame procedure using an atomic absorption spectrometry (model Hitachi8100).

3 Quantitative determination of linoleic acid in acylceramide:

Separation of epidermis was carried out by a heat treatment method;extraction of lipid by a Folch method; and fractionation of ceramide bya thin layer chromatography. Concentration of fatty acid (linoleic acid)in acylceramide closely relates to moisture-maintaining ability andbarrier function of keratin, and thus was measured as an indicator ofrough, dry skin symptom [B. B. A, 834 (1985) 357-363, Elsevier].

Quantitative determination of fatty acid in acylceramide was carried outby gas chromatography after the hydrolysis with methanol/NaOH and methylesterification with hydrochloric acid and methanol.

(Test results)

Test results are shown in Tables 3, 4 and 5 and FIGS. 3, 4 and 5.

                  TABLE 3                                                         ______________________________________                                        Average TEWL value and effect on improvement of rough, dry skin                             Average TEWL value                                                                          Degree of                                         Sample        (g/m.sup.2.hr)                                                                              improvement                                       ______________________________________                                        EPA (Zn:3.5 ppm)                                                                            13.0 ± 5.0 25% (1/4)                                         DHA (Zn:3.5 ppm)                                                                             17.2 ± 15.4                                                                             50% (2/4)                                         Control 1     27.5 ± 9.8  0% (0/4)                                         (Zn:3.5 ppm)                                                                  Control 2      2.5 ± 1.1 100% (4/4)                                        (Zn:20 ppm)                                                                   ______________________________________                                    

                  TABLE 4                                                         ______________________________________                                        Epidermal zinc concentration                                                  Sample         Epidermal zinc concentration (ppm)                             ______________________________________                                        EPA (Zn: 3.5 ppm)                                                                            158.8 ± 42.2                                                DHA (Zn: 3.5 ppm)                                                                            166.1 ± 20.9                                                Control 1 (Zn: 3.5 ppm)                                                                      108.9 ± 11.6                                                Control 2 (Zn: 20 ppm)                                                                       198.0 ± 23.5                                                ______________________________________                                    

                  TABLE 5                                                         ______________________________________                                        Linoleic acid concentration in ceramide                                       Sample         Linoleic acid concentration (ppm)                              ______________________________________                                        EPA (Zn: 3.5 ppm)                                                                            30.9 ± 1.48                                                 DHA (Zn: 3.5 ppm)                                                                            39.3 ± 2.16                                                 Control 1 (Zn: 3.5 ppm)                                                                      26.6 ± 5.60                                                 Control 2 (Zn: 20 ppm)                                                                       36.3 ± 2.68                                                 ______________________________________                                    

We claim:
 1. An oral dermatitis-curing composition comprising an orallyeffective amount of (A) a zinc compound and (B) docosahexaenoic acid oran ester thereof as effective components.